Treatment Developments Shaking Up Landscape for Nonmetastatic CRPC

Mark J. Mann, MD

There have not been designated novel treatment options for patients with nonmetastatic castration-resistant prostate cancer (CRPC) until very recently, explains Mark J. Mann, MD.

According to the American Urological Association (AUA) guidelines, patients with nonmetastatic CRPC should be observed with continued androgen deprivation therapy (ADT). Alternative treatment can include first-generation antiandrogens, such as flutamide, bicalutamide (Casodex), and nilutamide (Nilandron), or first-generation androgen synthesis inhibitors, such as ketoconazole plus a steroid. Clinicians should not offer systemic chemotherapy or immunotherapy to these patients, according to these guidelines.¹

Due to the stagnant treatment landscape, the February 2018 FDA approval of apalutamide (Erleada) for patients with nonmetastatic CRPC has been exciting for both patients and treating physicians. The approval is based the results of the phase III SPARTAN trial, in which apalutamide reduced the risk of metastasis or death by 72% in this patient population. The median metastasis-free survival (MFS) was 40.5 months in the apalutamide arm versus 16.2 months in the placebo arm (HR, 0.28; 95% CI, 0.23-0.35; P <.0001). At a median follow-up of 20.3 months, 61% of the apalutamide arm remained on treatment compared with 30% of patients receiving placebo. An interim overall survival (OS) analysis of 24% of events revealed a trend favoring apalutamide.²

In March 2018, the FDA granted a priority review to a supplemental new drug application for enzalutamide (Xtandi) for the treatment of men with nonmetastatic CRPC. The decision was based on phase III data of the PROSPER trial, in which the combination of enzalutamide plus ADT reduced the risk of metastases or death by 71% versus ADT alone.³ Additionally, the median MFS was 36.6 months with enzalutamide plus ADT versus 14.7 months with ADT alone (HR, 0.29; 95% CI, 0.24-0.35; P <.0001).

OncLive^®: Please provide an overview of your lecture on the treatment of nonmetastatic CRPC.

In an interview during the 2018 OncLive^® State of the Science Summit™ on Prostate Cancer, Mann, an assistant professor of urology at Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, discussed the developing treatment landscape for patients with nonmetastatic CRPC.Mann: The definition of nonmetastatic CRPC is a patient with a prostate-specific antigen (PSA) that is 2 over the nadir, or a 25% increase from the nadir while the testosterone is still repressed. The next part of the diagnosis is determining whether it is metastatic. That is done with a CT scan and a bone scan, which are standard, but there are new imaging modalities that are starting to come into play, specifically PET scans.

Can you discuss the current AUA guidelines?

Can you speak to the importance of the apalutamide approval and the background of the study?

Apalutamide has also recently been added to the National Comprehensive Cancer Network guidelines. Can you discuss this?

What are some of the challenges that remain with apalutamide?

The next step in surveillance is to make sure the patient [has] nonmetastatic disease. We discussed the AUA recommendations for treatment, or rather the lack of treatment, and the indication where we will then progress to more advanced treatments. I also discussed the latest ASCO publicized studies, such as enzalutamide in the PROSPER trial and apalutamide in the SPARTAN study.The current AUA guidelines for nonmetastatic CRPC is to continue with ADT. If the patients are not willing or do not accept those recommendations, then you can offer them a first-generation antiandrogen, such as bicalutamide, or a first-generation androgen synthesis inhibitor along with a steroid. The guidelines also are clear that they do not recommend chemotherapy or immunotherapy in those patients.The SPARTAN trial was for nonmetastatic CRPC, where patients could have been clinically N0 or N1, which indicates that they may have had more advanced disease in that trial. This trial randomized patients to apalutamide with ADT or ADT alone. They found that OS endpoints were not met and the time of progression to metastatic disease was approximately 44 months compared with less than 1.5 years in the ADT group alone.Apalutamide is an interesting drug in that it is a nextgeneration androgen receptor inhibitor. It targets the receptor, the signaling cascade, and DNA, binding with fewer central nervous system toxicities.It will be interesting to see its efficacy when broken down into racial differentials to determine how effective it is in patients with different ethnicities. Furthermore, it will be interesting to see how it affects the cascade of drugs that typically follows and how it plays into that role.

What are some other agents that are now being explored in this setting?

Once patients have entered this space where previously docetaxel and abiraterone acetate (Zytiga) were never present before, it will be interesting to see how they affect subsequent outcomes and whether patients have been previously treated with those drugs or not.Enzalutamide is the other major agent that was presented at the 2018 Genitourinary Cancers Symposium. They did a very similar design [to SPARTAN], except that was just in a nodal-negative [N0] and in an M0 population. They also had an increase in time to development of metastasis. It was not quite as long [as apalutamide] but still impressive. That is another drug that has shown efficacy in this space.

What are your thoughts on immunotherapy trying to make a breakthrough in this landscape?

There are other drugs being explored. There is potential for PARP inhibitors and immunotherapies that are currently being explored, as well.Immunotherapy hit the prostate cancer market far too early. Sipuleucel-T [Provenge] was far ahead of the immunotherapy game when it was first developed and approved. We know from the approval of many other immunotherapies that PSA progression and evaluating outcomes purely based on PSA values can be misleading. For example, in PD-1/PD-L1 inhibitors, you will often see a response, but radiographically you will see the opposite. It is reasonable to expect that from immunotherapies as well, which is why I suspect that sipuleucel-T may not have been adopted early on.

The more recent immunotherapies have shown some efficacy, but that activity is limited in prostate cancer. There are some interesting viral gene transfection therapies that are currently in the very early stages of being explored that may have some potential.

What are the differences in treatment for a patient with nonmetastatic CRPC versus nonmetastatic castration-sensitive prostate cancer?

Now that we understand how immunotherapies work and whether there is a flare phenomenon radiographically or by PSA, they may still be effective. We may be able to evaluate more important outcome markers, such as the MFS that the apalutamide and enzalutamide trials use as one of their primary endpoints.The difference with nonmetastatic castration-sensitive prostate cancer is that the treatment options [for that setting] have been standardized for a long time. ADT has been the mainstay of therapy. However, if a patient has CRPC, the difficulty is that the studies have not shown many effective treatment options until recently. They have looked at denosumab (Xgeva), which did not show any efficacy, and zoledronic acid, which showed a similar response.

With the newer imaging modalities, the question is whether a patient is really nonmetastatic. [Techniques such as] Gallium-68 PSMA (prostate-specific membrane antigen)—PET/CT scans identify metastatic disease when we did not think there was any. That is likely to change the nonmetastatic castration-sensitive and nonmetastatic CRPC playing fields. [For castration-sensitive disease], physicians should potentially use drugs from the STAMPEDE and LATITUDE trials.

The greater problem that this presents is that trials have been based on the same imaging diagnostic modalities. A large part of them have already been metastatic, so we are going to realize now that some of them are nonmetastatic. Should we look again at denosumab and zoledronic acid based on these new imaging modalities? I am not sure.

References

1. American Urological Association. Castration-resistant prostate cancer. American Urological Association website. auanet.org/guidelines/castration-resistant-prostate-cancer-(2013-amended-2015). Published 2013. Accessed March 22, 2018.
2. Small EJ, Saad F, Chowdhury S et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2018;36(suppl 6s;abstr 161). ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_ suppl.161.
3. Hussain M, Fizazi K, Saad F, et al. PROSPER: a phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36(suppl 6S;abstr 3). ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_suppl.3.